ES2249384T3 - Espiro(isobenzofuran-1,4'-piperadin)-3-onas y 3h-espirobenzofuran-1,4-piperidinas. - Google Patents
Espiro(isobenzofuran-1,4'-piperadin)-3-onas y 3h-espirobenzofuran-1,4-piperidinas.Info
- Publication number
- ES2249384T3 ES2249384T3 ES01270536T ES01270536T ES2249384T3 ES 2249384 T3 ES2249384 T3 ES 2249384T3 ES 01270536 T ES01270536 T ES 01270536T ES 01270536 T ES01270536 T ES 01270536T ES 2249384 T3 ES2249384 T3 ES 2249384T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- isobenzofuran
- spiro
- piperidin
- halogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 198
- 108010046593 Neuropeptide Y5 receptor Proteins 0.000 claims abstract description 109
- 102000028582 Neuropeptide Y5 receptor Human genes 0.000 claims abstract description 109
- 238000000034 method Methods 0.000 claims abstract description 51
- 230000027455 binding Effects 0.000 claims abstract description 50
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 48
- 208000035475 disorder Diseases 0.000 claims abstract description 26
- 238000000338 in vitro Methods 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 10
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 8
- 208000020016 psychiatric disease Diseases 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 93
- -1 hydroxy, amino Chemical group 0.000 claims description 86
- 229910052736 halogen Inorganic materials 0.000 claims description 73
- 150000002367 halogens Chemical class 0.000 claims description 70
- 229910052739 hydrogen Inorganic materials 0.000 claims description 58
- 239000001257 hydrogen Substances 0.000 claims description 58
- 101710151321 Melanostatin Proteins 0.000 claims description 57
- 239000000203 mixture Substances 0.000 claims description 57
- 125000001188 haloalkyl group Chemical group 0.000 claims description 48
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 48
- 101150111774 NPY5R gene Proteins 0.000 claims description 47
- 101100460788 Arabidopsis thaliana NPY5 gene Proteins 0.000 claims description 46
- 125000001424 substituent group Chemical group 0.000 claims description 46
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 45
- 102000005962 receptors Human genes 0.000 claims description 43
- 108020003175 receptors Proteins 0.000 claims description 43
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 41
- 238000002360 preparation method Methods 0.000 claims description 38
- 125000003545 alkoxy group Chemical group 0.000 claims description 37
- 150000002431 hydrogen Chemical class 0.000 claims description 33
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 30
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 29
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 27
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 26
- 239000003795 chemical substances by application Substances 0.000 claims description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 125000002837 carbocyclic group Chemical group 0.000 claims description 23
- 125000000304 alkynyl group Chemical group 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 15
- 239000000651 prodrug Substances 0.000 claims description 14
- 229940002612 prodrug Drugs 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 125000001544 thienyl group Chemical group 0.000 claims description 14
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 13
- 230000004913 activation Effects 0.000 claims description 12
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000002971 oxazolyl group Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 12
- 125000000335 thiazolyl group Chemical group 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 11
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- 239000001301 oxygen Substances 0.000 claims description 11
- 125000004193 piperazinyl group Chemical group 0.000 claims description 11
- 238000001514 detection method Methods 0.000 claims description 10
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- 229940079593 drug Drugs 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
- 238000000670 ligand binding assay Methods 0.000 claims description 8
- 229910052720 vanadium Inorganic materials 0.000 claims description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 125000002757 morpholinyl group Chemical group 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
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- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 7
- 125000001425 triazolyl group Chemical group 0.000 claims description 7
- 229910052727 yttrium Inorganic materials 0.000 claims description 7
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- IRDOMFKPNLFWGW-UHFFFAOYSA-N 1'-(6-methyl-1h-benzimidazol-2-yl)spiro[2-benzofuran-3,4'-piperidine]-1-one Chemical compound O1C(=O)C2=CC=CC=C2C1(CC1)CCN1C1=NC2=CC(C)=CC=C2N1 IRDOMFKPNLFWGW-UHFFFAOYSA-N 0.000 claims description 6
- JIVDRBRZFUEQBM-UHFFFAOYSA-N 1'-(6-pyridin-3-yl-1h-benzimidazol-2-yl)spiro[2-benzofuran-3,4'-piperidine]-1-one Chemical compound C12=CC=CC=C2C(=O)OC1(CC1)CCN1C(NC1=CC=2)=NC1=CC=2C1=CC=CN=C1 JIVDRBRZFUEQBM-UHFFFAOYSA-N 0.000 claims description 6
- RDDZTNYXWFDDJZ-UHFFFAOYSA-N 1'-[6-(trifluoromethyl)-1h-imidazo[4,5-b]pyridin-2-yl]spiro[2-benzofuran-3,4'-piperidine]-1-one Chemical compound O1C(=O)C2=CC=CC=C2C1(CC1)CCN1C1=NC2=NC=C(C(F)(F)F)C=C2N1 RDDZTNYXWFDDJZ-UHFFFAOYSA-N 0.000 claims description 6
- FGCDLQZYHPYSSV-UHFFFAOYSA-N 1'-[6-(trifluoromethylsulfonyl)-1h-benzimidazol-2-yl]spiro[2-benzofuran-3,4'-piperidine]-1-one Chemical compound O1C(=O)C2=CC=CC=C2C1(CC1)CCN1C1=NC2=CC(S(=O)(=O)C(F)(F)F)=CC=C2N1 FGCDLQZYHPYSSV-UHFFFAOYSA-N 0.000 claims description 6
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 6
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 229910052721 tungsten Inorganic materials 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- CLDMDFGJPGYXPI-UHFFFAOYSA-N 1'-(6-acetyl-1h-benzimidazol-2-yl)spiro[2-benzofuran-3,4'-piperidine]-1-one Chemical compound O1C(=O)C2=CC=CC=C2C1(CC1)CCN1C1=NC2=CC(C(=O)C)=CC=C2N1 CLDMDFGJPGYXPI-UHFFFAOYSA-N 0.000 claims description 4
- LPOLBQTZZHSRGO-UHFFFAOYSA-N 1'-(6-propylsulfonyl-1h-benzimidazol-2-yl)spiro[2-benzofuran-3,4'-piperidine]-1-one Chemical compound O1C(=O)C2=CC=CC=C2C1(CC1)CCN1C1=NC2=CC(S(=O)(=O)CCC)=CC=C2N1 LPOLBQTZZHSRGO-UHFFFAOYSA-N 0.000 claims description 4
- RQMKJTJDJCTLMI-UHFFFAOYSA-N 1'-[6-(1,3-oxazol-2-yl)-1h-benzimidazol-2-yl]spiro[2-benzofuran-3,4'-piperidine]-1-one Chemical compound C12=CC=CC=C2C(=O)OC1(CC1)CCN1C(NC1=CC=2)=NC1=CC=2C1=NC=CO1 RQMKJTJDJCTLMI-UHFFFAOYSA-N 0.000 claims description 4
- XWCWKHBTXAFSRD-UHFFFAOYSA-N 2-(3-oxospiro[2-benzofuran-1,4'-piperidine]-1'-yl)-3h-benzimidazole-5-carbonitrile Chemical compound C12=CC=CC=C2C(=O)OC11CCN(C=2NC3=CC=C(C=C3N=2)C#N)CC1 XWCWKHBTXAFSRD-UHFFFAOYSA-N 0.000 claims description 4
- XVMIZJDINZCQRH-UHFFFAOYSA-N C1=CN=C2NC=NC2=C1.C12=CC=CC=C2C(=O)OC21CCNCC2 Chemical compound C1=CN=C2NC=NC2=C1.C12=CC=CC=C2C(=O)OC21CCNCC2 XVMIZJDINZCQRH-UHFFFAOYSA-N 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 4
- 239000012530 fluid Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000003003 spiro group Chemical group 0.000 claims description 4
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
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- FSMWTPVKAMLPSN-UHFFFAOYSA-N 1'-(4,6-dichloro-1h-benzimidazol-2-yl)spiro[2-benzofuran-3,4'-piperidine]-1-one Chemical compound O1C(=O)C2=CC=CC=C2C1(CC1)CCN1C1=NC2=CC(Cl)=CC(Cl)=C2N1 FSMWTPVKAMLPSN-UHFFFAOYSA-N 0.000 claims description 3
- QGOAHRMVFCYWPZ-UHFFFAOYSA-N 1'-(5,6-difluoro-1h-benzimidazol-2-yl)spiro[2-benzofuran-3,4'-piperidine]-1-one Chemical compound O1C(=O)C2=CC=CC=C2C1(CC1)CCN1C1=NC(C=C(C(=C2)F)F)=C2N1 QGOAHRMVFCYWPZ-UHFFFAOYSA-N 0.000 claims description 3
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- JNDLYOIUCCIUON-UHFFFAOYSA-N 1'-(6-pyrazin-2-yl-1h-benzimidazol-2-yl)spiro[2-benzofuran-3,4'-piperidine]-1-one Chemical compound C12=CC=CC=C2C(=O)OC1(CC1)CCN1C(NC1=CC=2)=NC1=CC=2C1=CN=CC=N1 JNDLYOIUCCIUON-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61P3/04—Anorexiants; Antiobesity agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
Landscapes
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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| ATE314371T1 (de) | 1998-11-10 | 2006-01-15 | Merck & Co Inc | Spiro-indole als y5-rezeptor antagonisten |
| OA12050A (en) * | 1999-09-30 | 2006-05-02 | Neurogen Corp | Certain alkylene diamine-substituted heterocycles. |
| HUP0202678A3 (en) * | 1999-09-30 | 2004-06-28 | Pfizer | Certain alkylene diamine-substituted pyrazolo[1,5,-a]-1,5-pyrimidines and pyrazolo[1,5-a]-1,3,5-triazines, pharmaceutical compositions containing them and their use |
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| AU2002220276A1 (en) * | 2000-12-12 | 2002-06-24 | Neurogen Corporation | Spiro(isobenzofuran-1,4'-piperidin)-3-ones and 3h-spiroisobenzofuran-1,4'-piperidines |
| US6900220B2 (en) * | 2001-01-02 | 2005-05-31 | Syntex (U.S.A.) Llc | Quinazolone derivatives as alpha 1A/B adrenergic receptor antagonists |
| WO2002094825A1 (en) * | 2001-05-22 | 2002-11-28 | Banyu Pharmaceutical Co., Ltd. | Novel spiropiperidine derivative |
| DE60231880D1 (de) * | 2001-08-07 | 2009-05-20 | Banyu Pharma Co Ltd | Spiro isobenzofurane als neuropeptid y rezeptor antagonisten |
| CA2403307A1 (en) * | 2001-10-23 | 2003-04-23 | Neurogen Corporation | Substituted 2-cyclohexyl-4-phenyl-1h-imidazole derivatives |
| AUPR975601A0 (en) * | 2001-12-24 | 2002-01-31 | Fujisawa Pharmaceutical Co., Ltd. | Quinazolinone derivatives |
| US7704995B2 (en) * | 2002-05-03 | 2010-04-27 | Exelixis, Inc. | Protein kinase modulators and methods of use |
| CA2484209C (en) * | 2002-05-03 | 2013-06-11 | Exelixis, Inc. | Protein kinase modulators and methods of use |
| US7405234B2 (en) * | 2002-05-17 | 2008-07-29 | Bristol-Myers Squibb Company | Bicyclic modulators of androgen receptor function |
| JP4496722B2 (ja) * | 2002-06-28 | 2010-07-07 | 萬有製薬株式会社 | 新規ベンズイミダゾール誘導体 |
| US7105526B2 (en) * | 2002-06-28 | 2006-09-12 | Banyu Pharmaceuticals Co., Ltd. | Benzimidazole derivatives |
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| EP1407774A1 (en) * | 2002-09-10 | 2004-04-14 | LION Bioscience AG | 2-Amino-4-quinazolinones as LXR nuclear receptor binding compounds |
| US7632858B2 (en) * | 2002-11-15 | 2009-12-15 | Bristol-Myers Squibb Company | Open chain prolyl urea-related modulators of androgen receptor function |
| CA2507742A1 (en) | 2002-11-29 | 2004-06-17 | Banyu Pharmaceutical Co., Ltd. | Novel azole derivatives |
| US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
| MXPA05009245A (es) | 2003-03-11 | 2005-10-19 | Pfizer Prod Inc | Nuevos compuestos de pirazina como inhibidores del factor de crecimiento transformante (tgf). |
| JP2009513502A (ja) | 2003-07-02 | 2009-04-02 | エフ．ホフマン−ラ ロシュ アーゲー | アリールアミン置換キナゾリノン化合物 |
| JP4765627B2 (ja) | 2003-09-22 | 2011-09-07 | Ｍｓｄ株式会社 | 新規ピペリジン誘導体 |
| WO2005030210A1 (en) * | 2003-09-26 | 2005-04-07 | Pfizer Products Inc. | Treatment of neurological disorders related to rapid eye movement (rem) sleep disturbances with npy y5 receptor antagonists |
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| US20030036652A1 (en) | 2003-02-20 |
| DE60115092D1 (de) | 2005-12-22 |
| US6566367B2 (en) | 2003-05-20 |
| BR0116113A (pt) | 2004-08-03 |
| MXPA03004245A (es) | 2003-09-22 |
| ATE310004T1 (de) | 2005-12-15 |
| JP2004520299A (ja) | 2004-07-08 |
| US6943199B2 (en) | 2005-09-13 |
| US20040072847A1 (en) | 2004-04-15 |
| WO2002048152A2 (en) | 2002-06-20 |
| DE60115092T2 (de) | 2006-03-30 |
| WO2002048152A3 (en) | 2003-05-08 |
| EP1347982B1 (en) | 2005-11-16 |
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